Osteoporosis

To consider the appropriateness of antiresorptive therapy (e.g. bisphosphonates, denosumab) including duration to reduce fracture risk in the management of osteoporosis.

Although not essential, consider the prescription of antiresorptive therapy to reduce the fracture risk when managing osteoporosis in postmenopausal women. Individuals who suffer hip and vertebral fractures (an important cause of morbidity) have a decreased life expectancy.^{110,319,320,321,322}

Generally:

• Offer treatment to individuals at risk of new or recurrent osteoporotic fragility fractures (fractures resulting from low-level trauma)
• Encourage an adequate intake of calcium and vitamin D through the normal diet but supplements may be necessary if dietary calcium is low, or vitamin D insufficiency is a risk^110,215

Bisphosphonates:

• Including alendronic acid, risedronate sodium, ibandronic acid and zoledronic acid, can be prescribed for reducing fracture risk in the treatment of osteoporosis, and can reduce the risk of vertebral, non-vertebral or hip fractures^{110,215,319,320,321,322,323,324,325,326,327,328,329}
• See NNT table for further detail
• Therapy is most likely to benefit those who have a life expectancy greater than 12.4 months,³²⁴ therefore consider likely life expectancy/prognosis when deciding whether to prescribe bisphosphonates for postmenopausal women with osteoporosis
• Oral bisphosphonates should be the first-line treatment therapy where appropriate for postmenopausal women and men over 50 years, at increased risk of fracture^{110,319,320,321,322,323,324}
• Oral bisphosphonates should be prescribed for at least five years before reassessing risk, or at least three years³²² for intravenous bisphosphonates
• Oral bisphosphonate can be prescribed for at least 10 years in people
  • over 70 years, with a previous history of a hip or vertebral fracture(s)
  • taking glucocorticoids equal or more than 7.5mg prednisolone per day (or equivalent)
  • who have experienced one or more fragility fractures during the first five years of treatment, when their treatment has not been changed³²²
• Zoledronic acid is an intravenous bisphosphonate which can be prescribed to prevent or reduce the risk of vertebral, non-vertebral and hip fractures in postmenopausal women who cannot tolerate oral bisphosphonates.¹¹⁰ It should be prescribed for at least three years in people over 70 years³²²
• Oral ibandronic acid can be considered for preventing vertebral fractures in postmenopausal women with osteoporosis¹¹⁰
• Ibandronic acid is not recommended to reduce non-vertebral or hip fracture risk^320,321
• Alendronic acid, risedronate sodium or zoledronic acid can be prescribed for prevention of vertebral fracture in men and women associated with glucocorticoid related risk^110,215
• Zoledronic acid can be prescribed for men in the treatment of osteoporosis for prevention of vertebral fractures.²¹⁵
• Risks of bisphosphonate treatment are gastrointestinal (GI) upset and oesophageal erosion and ulcers, therefore use with caution in those with upper GI problems. Avoid use of alendronic acid and oral ibandronic acid in those with stricture or achalasia, however, risedronate can be used with caution^110,215
• When selecting drugs to reduce the risk of fractures in postmenopausal women, and men older than 50 years, alternative treatment options should be available if first-line bisphosphonates are unsuitable or not tolerated³²²

Denosumab:

• When bisphosphonates are contra-indicated or there is an intolerance, denosumab should be prescribed (if appropriate) to prevent vertebral, non-vertebral and hip fractures in postmenopausal women with dual-energy X-ray absorptiometry (DXA)-proven osteoporosis110
• When prescribing denosumab, serum calcium should be checked two weeks before treatment, and for individuals with renal impairment (eGFR <30ml/min), this should be checked again a fortnight after therapy.110 Individuals should be encouraged to report symptoms indicative of hypocalcaemia, such as muscle spasms or tingling in hands or face.
• Denosumab therapy should continue for five years and possibly up to 10 years if the individual is at high risk of fracture^{110,320,321,322}
• Denosumab prescribed in people older than 75 years can reduce the risk of new vertebral fractures, but not non-vertebral fractures^330,331
• When denosumab is discontinued, other antiresorptive therapy should be prescribed, for example, an intravenous infusion of zoledronic acid six months after the last dose (if bisphosphonates are not contra-indicated). This prevents the rebound increase in bone turnover, reducing the chance of rapid bone mineral density loss and increased fracture risk.³²²

Check on adherence to therapy as treatment benefits will not be obvious to individuals taking it. Healthcare professionals (HCP) should be aware that adherence to a range of treatments decreases over time.³²⁶ Bisphosphonates may be given weekly rather than daily to aid adherence.

Withdrawal from antiresorptive treatment is common due to adverse effects.³²³

Consider measuring bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) scanning after an interval of three years to assess response to treatment in postmenopausal women on alendronic acid, ibandronic acid, and zoledronic acid or denosumab therapy.¹¹⁰ Consider this on a case-by-case basis, where adherence with treatment is of concern.

Continue antiresorptive treatment in those with a high risk of osteoporotic fragility fracture, including those aged over 75 years or with a previous hip or vertebral fracture.^110,328

Do not stop denosumab without specialist advice.³³²

Bisphosphonate tablets should be swallowed whole with a full glass of water, on an empty stomach and it is important to remain upright (seated or standing) for at least 30 minutes after administration.²¹⁵

Bisphosphonates are contra-indicated in the presence of hypocalcaemia, which should first be treated.^215,322

A dental check is advised before the person starts treatment. Those with poor dental status should be assessed by a dentist and have necessary remedial work performed prior to commencing bisphosphonate or denosumab therapy. After starting treatment, people should continue with good dental hygiene, receive routine dental check-ups and report any dental symptoms such as pain or swelling.¹¹⁰ The risk of osteonecrosis of the jaw is related to the potency of the bisphosphonate (highest for zoledronic acid), route of administration (IV highest), cumulative dose and duration.²¹⁵

Atypical femoral fractures have been rarely reported with bisphosphonate and denosumab treatment.^110,215,322 Individuals should report thigh, hip or groin pain and if these symptoms change, the femur should be imaged (by full-length femur X-ray, isotope scanning or MRI).³²² The need to continue treatment should be re-evaluated periodically balancing risks against benefits.

Ear pain, discharge from the ear or an ear infection during bisphosphonate treatment should be reported. Benign idiopathic osteonecrosis of the external auditory canal has been reported very rarely.²¹⁵

Risedronate should be used with caution if the person has delayed oesophageal emptying.¹¹⁰

1. People who stop taking regular or repeated courses of oral corticosteroids may be able to stop osteoporosis prevention treatment (reassess risk of osteoporotic fractures using online tools).²¹⁵
2. People taking bisphosphonates for osteoporosis, should have their fracture risk reassessed after three to five years, and women should continue treatment if they remain at high risk of fractures.^320,321
3. Low-to-moderate risk patients who are stable (those who have not experienced a fracture) after five years of taking oral bisphosphonates or, after three years with intravenous zoledronic acid, may be considered for a ‘drug holiday’.³¹⁹ Intervention thresholds are described by the National Osteoporosis Guideline Group-UK (NOGG) to guide whether a treatment can be stopped for a period of time.³³³
4. Prescribers should be cautious about discontinuing alendronic acid, zoledronic acid or risedronate, because of the risk of bone mineral density reduction at the hip and lumbar spine, and because of the increased risk of vertebral fracture after discontinuation. However, some studies show that fracture risk after discontinuation of alendronic acid, zoledronic acid or risedronate in those who have had adherence rates of greater than or equal to 50% over three years, might be less than those who persist on therapy.³²⁷ Other risk factors such as advanced age, current smoking and a history of falls were predictive of BMD decrease or new fractures after discontinuation.³²⁷
5. Discontinuation of alendronic acid can change BMD at the femoral neck, total hip and distal third of the forearm after five years. However, after 10 years of follow-up, mean BMD remained at or above pre-treatment levels, whether treatment was continued or not.³²⁷
6. Discontinuation of zoledronic acid after three or six years does not make a difference to osteoporotic fractures.³²⁷
7. Because the benefits for bone remodelling with denosumab are reversed after six months, a ‘drug holiday’ is not suggested, therefore if stopping denosumab, to avoid a treatment gap, the person should receive other antiresorptive treatment to prevent rapid bone mineral density loss, increased fracture risk, or a rebound in bone turnover, for example an annual intravenous dose of zolendronate.^{320,321,322,330} Those who have discontinued denosumab without seeking medical advice first should be referred urgently to the local Bone Health/Mineral Metabolism Clinic, including those who are over one month late for their six-monthly injection.
8. Zoledronic acid and risedronate are contra-indicated in severe renal impairment (eGFR ≤35ml/min and ≤30ml/min, respectively), whilst alendronic acid and ibandronic acid are cautioned against (eGFR ≤35ml/min and ≤30ml/min, respectively).^110,215
9. Those with severe renal impairment (eGFR 15-29ml/min) or receiving dialysis are at a greater risk of developing hypocalcaemia with denosumab and monitoring of calcium levels is recommended.²¹⁵

Supporting people who do not or cannot reduce/stop

Reinforce the advice regarding long-term safety and symptoms to report (dental pain, thigh, hip or groin pain and ear pain).

In women receiving bisphosphonate adjuvant therapy as part of breast cancer treatment, do not stop this treatment without first consulting their oncology team.

Specific areas/situations where medication may need to be introduced or increased

Individuals taking prednisolone 7.5mg daily for three months or more should be offered antiresorptive treatment. This includes those taking repeated short courses of prednisolone (three or more in 12 months).^110,215

If a fracture occurs whilst on bisphosphonate treatment, ask about adherence to treatment. If adherence is assured, then secondary causes for the fracture should be explored.³²²

If a new fracture occurs after bisphosphonate treatment is discontinued, the person should be reassessed.³²²

If no new fracture occurs after bisphosphonate discontinuation, the person should receive a fracture risk assessment at two-to-four-year intervals to determine if treatment should be restarted.^320,321

If BMD significantly declines, or if factors alter the person’s clinical risk; consider reinitiating therapy earlier.^320,321

Does the person understand the outcomes of the review, including risk and benefits?

• Explain the risk of fractures without treatment and the benefits versus risk of commencing preventative osteoporosis treatment
• Oral bisphosphonates must be taken on an empty stomach as their absorption is affected by food, drink and other drugs. They must be taken with plain water 30 minutes before the first food, other medication or drink of the day. If this is not possible, then they should be taken at least two hours before or at least two hours after any food, other medication or drink (other than plain water). They must remain upright (seated or standing) for 30 minutes afterwards to reduce the likelihood of GI adverse effects^110,215
• Poor adherence with bisphosphonate therapy increases fracture risk
• Symptoms indicative of adverse effects (dental pain, thigh, hip or groin pain and ear pain)

Is drug therapy tailored to the individual?

• Increasing weight-bearing physical activity, stopping smoking and reducing alcohol intake are important lifestyle changes which will help to prevent osteoporosis and fragility fractures
• Highlight the importance of adherence to therapy in the absence of immediately obvious benefits.¹¹⁰ Alternative formulations, such as once weekly formulations for bisphosphonates are available which may be helpful for adherence and are taken on the same day each week
• If a person has a multi-compartment compliance aid (MCA), the bisphosphonate should be packaged separately, in their original packaging, due to the special considerations required for taking the medication³³⁴

Agree the plan

• Explain that if there are any new fractures, then the treatment plan will be reviewed
• Treatment will be reviewed on a regular basis to check that it is still appropriate
• If a carer is assisting with administration of medication, ensure they are aware of the advice regarding timing of administration

• self-management/support tools
• decision aids

The Royal Osteoporosis Society produce information and support for people to help with bone health, including an osteoporosis risk checker.

There is a patient decision aid produced by NICE. Bisphosphonates for treating osteoporosis patient decision aid (nice.org.uk)

Decision support tools to assist in determination of risk of fracture are available:¹¹⁰

• FRAX tool
• Qfracture tool

Algorithms to assist in detection and management of osteoporosis are available. Figure 10 shows the algorithm from SIGN 142.¹¹⁰ Local examples are also available in clinical handbooks

The figure below is reproduced from: Scottish Intercollegiate Guidelines Network (SIGN). Management of osteoporosis and the prevention of fragility fractures. Edinburgh: SIGN; 2021. (SIGN publication no.142). Figure available on the SIGN website.¹¹⁰

Pathway from risk factors to pharmacological treatment selection in postmenopausal women over the age of 50

*DEXA scan advisable to obtain baseline BMD but not necessary to initiate treatment

⁺one severe or two or more moderate vertebral fractures on x-ray, and T-score less than or equal to 1.5 at any site or spine T score less than or equal to 4.0.

National Therapeutic Indicators (NTIs) use prescription data in specific areas to provide a measure of prescribing activity for comparison across NHS Boards, Health and Social Care Partnerships (HSCPs), GP clusters and GP practices.

NTIs are available to view online.

NTIs benchmark prescribing across set parameters and are presented in a variety of ways. Examining variation over time can indicate where improvements in prescribing can be made. The indicator detail provides further information and suggested actions.

Indicators for this hot topic include:

• Number of people prescribed a long-term oral steroid without co-prescription of a bone protecting agent as a percentage of all people prescribed a long-term oral steroid. See the chart below.

Number of people prescribed a long-term oral steroid without co-prescription of a bone protecting agent as a percentage of all people prescribed a long-term oral steroid

(Click on image to enlarge)